Modeling Sweet Protein-Receptor Interactions

模拟甜味蛋白-受体相互作用

基本信息

批准号：
7742608
负责人：
MENG CUI
金额：
$ 22.2万
依托单位：
VIRGINIA COMMONWEALTH UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-12-01 至 2011-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7742608
关键词：
Acetylcholinesterase Agreement Aspartame Binding Binding Sites Biochemistry Cattle Cebidae Cercopithecidae Charybdotoxin Chimera organism Complex Cyclamates Cysteine-Rich Domain Diabetes Mellitus Docking Electrostatics Epidemic Equation Extracellular Domain Family G Protein-Coupled Receptor Genes G-Protein-Coupled Receptors Gadolinium Glutamates Goals Homology Modeling Human Journals Lead Ligand Binding Ligands Maps Metabotropic Glutamate Receptors Methods Modeling Molecular Molecular Conformation Mus Mutagenesis Nature Obesity Potassium Channel Proteins Recovery Research Proposals Rest Rhodopsin Rodent Role Scorpions Simulate Site Site-Directed Mutagenesis Structure Sweetening Agents Testing Time Toxin Transmembrane Domain Venus Flytrap base design fasciculin improved inhibitor/antagonist mutant neotame programs public health relevance receptor receptor function research study response simulation success sugar sweet receptor sweet taste perception

项目摘要

DESCRIPTION (provided by applicant): Modeling Sweet Protein-Receptor Interactions The goal of this research proposal is to understand the nature of the interactions between sweet proteins and sweet taste receptor (STR). STR is a heterodimer of T1R2 and T1R3, which is a G protein-coupled receptor (GPCRs) from Family C. Growing evidence shows that STR has multiple ligand binding sites for different sweeteners. Although no crystal structure of STR is available at this time, homology models of STR can be developed based on the appropriate templates. The Venus Flytrap Module (VFTM) and Cysteine Rich Domain (CRD) can be modeled based on the crystal structures of metabotropic glutamate receptors (mGluRs). Transmembrane Domain (TMD) of T1R2 and T1R3 can be modeled based on the crystal structure of bovine rhodopsin. We have successfully used homology models of the sweet taste receptors, molecular docking of sweet ligands to the receptors, and site-directed mutagenesis of the receptors to identify potential ligand binding sites of the sweet taste receptor. Our studies show that the VFTM of hT1R2 is the binding site for sweeteners aspartame and neotame, while the TMD of hT1R3 is the binding site for the sweetener cyclamate and the sweet inhibitor lactisole. Recent chimera and mutagenesis studies show that both the VFTM and CRD of STR are involved in sweet protein-receptor interactions. To investigate the interactions of sweet proteins with STR we propose to construct models of the VFTM-CRD in complex with sweet proteins. The crystal structures of the VFTM-CRD of mGluR-I/II, which were resolved recently, provide us an ideal template to develop homology models for the VFTM-CRD of STR. Here we propose to develop several VFTM-CRD of STR homology models, which represent different conformational states, based on the crystal structures of mGluR templates. The refined VFTM-CRD models of STR will be used for docking the sweet proteins by Brownian Dynamics (BD) simulations to understand sweet protein-receptor interactions. In combination with site-directed point mutational experiments and BD docking simulations, we will identify potential complexes of the VFTM-CRD of STR with sweet proteins. The predicted complexes models will be tested via mutagenesis studies to assess the success of the predictions. These studies should lead to a better understanding the function mechanism of STR. PUBLIC HEALTH RELEVANCE: Obesity and diabetes have reached epidemic proportions in developedsocieties. Replacing sugar with low-or non-caloric sweeteners may be of benefit. To design moreeffective sweeteners it is important to understand at the molecularlevel how the sweet taste receptor functions.

描述（由申请人提供）：建模甜蛋白质受体相互作用该研究建议的目的是了解甜蛋白与甜味味受体（STR）之间相互作用的性质。 STR是T1R2和T1R3的异二聚体，它是来自家族的G蛋白偶联受体（GPCR）C。越来越多的证据表明，STR具有多个适合不同甜味剂的配体结合位点。尽管目前尚无STR的晶体结构，但可以根据适当的模板开发STR的同源模型。可以根据代谢性谷氨酸受体（MGLURS）的晶体结构对金星飞带模块（VFTM）和富含半胱氨酸的域（CRD）进行建模。 T1R2和T1R3的跨膜结构域（TMD）可以基于牛Rhodopsin的晶体结构进行建模。我们成功地使用了甜味受体的同源模型，甜味配体的分子对接对受体的分子对接以及受体的定位诱变，以鉴定甜味受体的潜在配体结合位点。我们的研究表明，HT1R2的VFTM是甜味剂Aspartame和Neotame的结合位点，而HT1R3的TMD是甜味剂cliganter cilclamate和甜抑制剂乳酸盐的结合位点。最近的嵌合体和诱变研究表明，STR的VFTM和CRD都与甜蛋白质受体相互作用有关。为了研究甜蛋白与STR的相互作用，我们建议将VFTM-CRD的模型与甜蛋白进行复合。最近解决的MGlur-I/II的VFTM-CRD的晶体结构为我们提供了一个理想的模板，以开发STR的VFTM-CRD同源模型。在这里，我们建议开发几种基于MGLUR模板的晶体结构，它们代表不同构象状态的VFTM-CRD。精制的STR的VFTM-CRD模型将用于通过Brownian Dynamics（BD）模拟来对接甜蛋白，以了解甜蛋白质受体相互作用。结合定位点突变实验和BD对接模拟，我们将确定STR的VFTM-CRD的潜在复合物与甜蛋白。预测的复合物模型将通过诱变研究测试，以评估预测的成功。这些研究应更好地理解STR的功能机制。公共卫生相关性：肥胖和糖尿病在发达国家中达到了流行比例。用低或非热甜味剂代替糖可能有益。要设计更有效的甜味剂，重要的是要在分子级别的甜味受体如何发挥作用上了解。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Molecular docking: a powerful approach for structure-based drug discovery.

DOI：
10.2174/157340911795677602
发表时间：
2011-06
期刊：
Current computer-aided drug design
影响因子：
1.7
作者：
Meng XY;Zhang HX;Mezei M;Cui M
通讯作者：
Cui M

Molecular mechanism of species-dependent sweet taste toward artificial sweeteners.

DOI：
10.1523/jneurosci.0791-11.2011
发表时间：
2011-07-27
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
0
作者：
Liu B;Ha M;Meng XY;Kaur T;Khaleduzzaman M;Zhang Z;Jiang P;Li X;Cui M
通讯作者：
Cui M

Predicting protein interactions by Brownian dynamics simulations.

DOI：
10.1155/2012/121034
发表时间：
2012
期刊：
Journal of biomedicine & biotechnology
影响因子：
0
作者：
Meng XY;Xu Y;Zhang HX;Mezei M;Cui M
通讯作者：
Cui M

Functional characterization of the heterodimeric sweet taste receptor T1R2 and T1R3 from a New World monkey species (squirrel monkey) and its response to sweet-tasting proteins.

DOI：
10.1016/j.bbrc.2012.09.083
发表时间：
2012-10-19
期刊：
BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
影响因子：
3.1
作者：
Liu, Bo;Ha, Matthew;Meng, Xuan-Yu;Khaleduzzaman, Mohammed;Zhang, Zhe;Li, Xia;Cui, Meng
通讯作者：
Cui, Meng

Computational approaches for modeling GPCR dimerization.

GPCR 二聚化建模的计算方法。